Nanoparticles, described in U.S. Pat. No. 5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic agent onto which are adsorbed a noncrosslinked surface modifier, and which have an average particle size of less than about 400 nanometers (nm).
Sterilization of therapeutic and diagnostic agents in nanocrystalline form stabilized by a surface modifier (surfactant) is difficult. Filtration using a filter of 0.22 .mu.m mesh size is sufficient to remove most bacteria and viruses, but the nanoparticles, due to their sizes, cannot be sterile filtered without accounting for substantial drug losses. Conventional autoclaving (steam heat) at 121.degree. C. generally results in substantial growth in particle size, rendering the resulting particles unusable. One possible explanation is that the aggregation of nanoparticles upon heating is related to the precipitation of the surface modifier (surfactant) at or below sterilization temperature (above the cloud point of the surfactant) where the bound surfactant molecules are likely to dissociate from the nanoparticles and precipitate, leaving the nanoparticles unprotected. The unprotected nanoparticles can then aggregate into clusters of particles. Upon cooling, the surfactant redissolves into the solution, which then coats the aggregated particles and prevents them from dissociating into smaller ones.
Shelf stability of nanoparticles is also a problem, with nanoparticle size increasing upon storage. It would be advantageous to allow for an increase in storage shelf life after autoclaving without the concomitant agglomeration of the nanoparticle suspension. It is desirable that the nanoparticles exhibit good physical stability, i.e., shelf stability and stability in biological fluids, both before and after autoclaving.
This invention is directed to novel compositions that allow autoclaving of nanoparticles with reduced or no particle size growth. These compositions provide for a surfactant adsorbed onto nanoparticles such that the nanoparticles do not agglomerate during autoclaving. This invention is also directed to a method of making such compositions.
This invention is also directed to novel compositions that allow autoclaving of nanoparticles without the concomitant increase in particle size upon storage, and a method of making such compositions.